The long term goal of this research is to develop clinically relevant multimodal MSN-based therapeutic strategies with the ability of overcoming chemo and stromal resistance to improve the final outcome of pancreatic ductal adenocarcinoma (PDAC) treatment. PDAC is the fourth leading cause of cancer death in the United States. This is one of the most difficult conditions to treat, with a 5-year survival at abot 6%. The horrific prognosis of PDAC is a result of late diagnosis and the tumor's refractory behavior toward current drug treatment. Mesoporous silica nanoparticles (MSNs) hold considerable promise as the next generation of nanomedicine that enables the early detection of disease, simultaneous monitoring and treatment, and targeted therapy with minimal toxicity. The hypothesis underlying this proposal is that by using MSNs as scaffold, we can combine different therapies such as chemotherapy, targeted therapy and combination therapy to overcome some of the main deficiencies in the current treatment of PDAC. The main target of this proposal is to develop multimodal MSN-based therapeutic strategies with the ability of overcoming chemo and stromal resistance to improve the final outcome of PDAC treatment. This goal will be accomplished by completion of three Specific Aims: 1) To develop novel MSN-based approaches for combinatorial chemotherapy and targeted therapy of PDAC; 2) To evaluate the in vivo biodistribution, pharmacokinetics, targeting ability and therapeutic efficacy of MSN materials developed in Aim 1; and 3) To develop MSN-based delivery platforms that combine chemotherapy and targeted therapy with stromal-depleting agents as novel strategies to improve PDAC treatment. The results of this work will lead to the development of several platforms with the ability of overcoming chemo and stromal resistance to improve the treatment of PDAC. Moreover; the in vivo results, obtained from a unique triplet transgenic PDAC mouse model, will provide the proof of concept to justify the evaluation of these platforms in clinical studies. These advancements in PDAC treatment will eventually impact the clinical care of this deadly disease.